The objectives of this project are to identify and characterize the mechanisms by which autosomal dominant, histocompatibility-linked immune response (Ir) genes regulate humoral and cell-mediated responses to T cell-dependent antigens. The immune responses by inbred strains of mice to the synthetic terpolymers L-glutamic acid-L-alanine-L-tyrosine (GAT) and L-glutamic acid-L-tyrosine (GT) and to heterologous insulins are two model systems currently under investigation. The immune responses to these antigens is all-or-none; that, some strains of mice respond whereas other do not. Continuing studies on the more well-characterized GAT system will focus on functional, serological and immunochemical differences between T cells and B cells from responder and nonresponder mice. The mechanisms of Ir gene control of responses to insulin are being characterized in vivo by adoptive transfer procedures. These studies have all been designed to test the hypothesis that nonresponsiveness to a particular antigen reflects a defect in cell-cell communication and furthermore, that such a defect can occur at any position in the pathway of cell-cell interactions that involve products of I-subregion genes. The identification of defects in genetic nonresponder mice should provide valuable insight into regulatory pathways that control the immunological network. In addition, insulin is a biologically active molecule of clinical relevance. It is well-established that insulin replacement therapy frequently results in complications caused by production of anti-insulin anntibodies by diabetics. Thus, the analysis of immune responses to insulin may contribute to the development of rational approaches for manipulation of the immune system to prevent specific antibody responses in insulin-dependent diabetic patients.